MicroRNAs and proteolytic cleavage of receptors in cancers: A comprehensive review of regulatory interactions and therapeutic implications.

Cancer remains a challenging disease worldwide, necessitating innovative approaches to better comprehend its underlying molecular mechanisms and devise effective therapeutic strategies. Over the past decade, microRNAs (miRNAs) have emerged as crucial players in cancer progression due to their regulatory roles in various cellular processes. Moreover, the involvement of unwanted soluble receptors has gained increasing attention because they contribute to tumorigenesis or drug resistance by disrupting normal signaling pathways and neutralizing ligands. This comprehensive review explores the intricate interplay between miRNAs and unwanted-soluble receptors in the context of cancer biology. This study provides an analysis of the regulatory interactions between miRNAs and these receptors, elucidating how miRNAs can either suppress or enhance their expression. MiRNAs can directly target receptor transcripts, thereby regulating soluble receptor levels. They also modulate the proteolytic cleavage of membrane-bound receptors into soluble forms by targeting sheddases, such as ADAMs and MMPs. Furthermore, the review delves into the therapeutic potential of manipulating miRNAs to modulate unwanted soluble receptors. Various strategies, including synthetic miRNA mimics or anti-miRNAs, hold promise for restoring or inhibiting miRNA function to counteract aberrant receptor activity. Moreover, exploring miRNA-based delivery systems may provide targeted and precise therapies that minimizing off-target effects. In conclusion, this review sheds light on the intricate regulatory networks involving miRNAs and unwanted soluble receptors in cancer biology thereby uncovering novel therapeutic targets, and paving the way for developing innovative anti-cancer therapies.

Understanding the prion-like behavior of mutant p53 proteins in triple-negative breast cancer pathogenesis: The current therapeutic strategies and future directions.

Breast cancer (BC) is viewed as a significant public health issue and is the primary cause of cancer-related deaths among women worldwide. Triple-negative breast cancer (TNBC) is a particularly aggressive subtype that predominantly affects young premenopausal women. The tumor suppressor p53 playsa vital role in the cellular response to DNA damage, and its loss or mutations are commonly present in many cancers, including BC. Recent evidence suggests that mutant p53 proteins can aggregate and form prion-like structures, which may contribute to the pathogenesis of different types of malignancies, such as BC. This review provides an overview of BC molecular subtypes, the epidemiology of TNBC, and the role of p53 in BC development. We also discuss the potential implications of prion-like aggregation in BC and highlight future research directions. Moreover, a comprehensive analysis of the current therapeutic approaches targeting p53 aggregates in BC treatment is presented. Strategies including small molecules, chaperone inhibitors, immunotherapy, CRISPR-Cas9, and siRNA are discussed, along with their potential benefits and drawbacks. The use of these approaches to inhibit p53 aggregation and degradation represents a promising target for cancer therapy. Future investigations into the efficacy of these approaches against various p53 mutations or binding to non-p53 proteins should be conducted to develop more effective and personalized therapies for BC treatment.

Non-apoptotic cell death programs in cervical cancer with an emphasis on ferroptosis.

BACKGROUND: Cervical cancer, a pernicious gynecological malignancy, causes the mortality of hundreds of thousands of females worldwide. Despite a considerable decline in mortality, the surging incidence rate among younger women has raised serious concerns. Immortality is the most important characteristic of tumor cells, hence the carcinogenesis of cervical cancer cells pivotally requires compromising with cell death mechanisms. METHODS: The current study comprehensively reviewed the mechanisms of non-apoptotic cell death programs to provide possible disease management strategies. RESULTS: Comprehensive evidence has stated that focusing on necroptosis, pyroptosis, and autophagy for disease management is associated with significant limitations such as insufficient understanding, contradictory functions, dependence on disease stage, and complexity of intracellular pathways. However, ferroptosis represents a predictable role in cervix carcinogenesis, and ferroptosis-related genes demonstrate a remarkable correlation with patient survival and clinical outcomes. CONCLUSION: Ferroptosis may be an appropriate option for disease management strategies from predicting prognosis to treatment.

The role of efferocytosis and transplant rejection: Strategies in promoting transplantation tolerance using apoptotic cell therapy and/or synthetic particles.

Recently, efforts have been made to recognize the precise reason(s) for transplant failure and the process of rejection utilizing the molecular signature. Most transplant recipients do not appreciate the unknown length of survival of allogeneic grafts with the existing standard of care. Two noteworthy immunological pathways occur during allogeneic transplant rejection. A nonspecific innate immune response predominates in the early stages of the immune reaction, and allogeneic antigens initiate a donor-specific adaptive reaction. Though the adaptive response is the major cause of allograft rejection, earlier pro-inflammatory responses that are part of the innate immune response are also regarded as significant in graft loss. The onset of the innate and adaptive immune response causes chronic and acute transplant rejection. Currently employed immunosuppressive medications have shown little or no influence on chronic rejection and, as a result, on overall long-term transplant survival. Furthermore, long-term pharmaceutical immunosuppression is associated with side effects, toxicity, and an increased risk of developing diseases, both infectious and metabolic. As a result, there is a need for the development of innovative donor-specific immunosuppressive medications to regulate the allorecognition pathways that induce graft loss and to reduce the side effects of immunosuppression. Efferocytosis is an immunomodulatory mechanism with fast and efficient clearance of apoptotic cells (ACs). As such, AC therapy strategies have been suggested to limit transplant-related sequelae. Efferocytosis-based medicines/treatments can also decrease the use of immunosuppressive drugs and have no detrimental side effects. Thus, this review aims to investigate the impact of efferocytosis on transplant rejection/tolerance and identify approaches using AC clearance to increase transplant viability.

Identification of a Missense Mutation in GJA8 Gene in an Iranian Family with Autosomal Dominant Congenital Cataract.

Purpose: To identify the causative mutations of autosomal dominant (AD) congenital cataracts in a large Iranian family. Methods: The complete and accurate family history and clinical information of participants were collected. A total of 51 family members, including 22 affected and 29 unaffected individuals, were recruited in this study. We performed whole exome sequencing to reveal pathogenic mutation. We used amplification refractory mutation system polymerase chain reaction and Sanger sequencing techniques to confirm segregation in patients and also to rule it out in the healthy participants. Results: A known missense mutation, c.827C>T (S276F), in GJA8 was identified. This mutation was confirmed in all patients. Neither all healthy family members nor 100 healthy individuals who served as controls from general population had this mutation. Conclusion: The missense mutation c. 827C>T in the GJA8 gene is associated with AD congenital lamellar cataract with complete penetrance in a six-generation Iranian family.

Recent advances and applications of peptide-agent conjugates for targeting tumor cells.

BACKGROUND: Cancer, being a complex disease, presents a major challenge for the scientific and medical communities. Peptide therapeutics have played a significant role in different medical practices, including cancer treatment. METHOD: This review provides an overview of the current situation and potential development prospects of anticancer peptides (ACPs), with a particular focus on peptide vaccines and peptide-drug conjugates for cancer treatment. RESULTS: ACPs can be used directly as cytotoxic agents (molecularly targeted peptides) or can act as carriers (guiding missile) of chemotherapeutic agents and radionuclides by specifically targeting cancer cells. More than 60 natural and synthetic cationic peptides are approved in the USA and other major markets for the treatment of cancer and other diseases. Compared to traditional cancer treatments, peptides exhibit anticancer activity with high specificity and the ability to rapidly kill target cancer cells. ACP's target and kill cancer cells via different mechanisms, including membrane disruption, pore formation, induction of apoptosis, necrosis, autophagy, and regulation of the immune system. Modified peptides have been developed as carriers for drugs, vaccines, and peptide-drug conjugates, which have been evaluated in various phases of clinical trials for the treatment of different types of solid and leukemia cancer. CONCLUSIONS: This review highlights the potential of ACPs as a promising therapeutic option for cancer treatment, particularly through the use of peptide vaccines and peptide-drug conjugates. Despite the limitations of peptides, such as poor metabolic stability and low bioavailability, modified peptides show promise in addressing these challenges. Various mechanism of action of anticancer peptides. Modes of action against cancer cells including: inducing apoptosis by cytochrome c release, direct cell membrane lysis (necrosis), inhibiting angiogenesis, inducing autophagy-mediated cell death and immune cell regulation.

Exosomal microRNAs and long noncoding RNAs: as novel biomarkers for endometriosis.

Endometriosis is a gynecological inflammatory disorder characterized by the development of endometrial-like cells outside the uterine cavity. This disease is associated with a wide range of clinical presentations, such as debilitating pelvic pain and infertility issues. Endometriosis diagnosis is not easily discovered by ultrasound or clinical examination. Indeed, difficulties in noninvasive endometriosis diagnosis delay the confirmation and management of the disorder, increase symptoms, and place a significant medical and financial burden on patients. So, identifying specific and sensitive biomarkers for this disease should therefore be a top goal. Exosomes are extracellular vesicles secreted by most cell types. They transport between cells' bioactive molecules such as noncoding RNAs and proteins. MicroRNAs and long noncoding RNAs which are key molecules transferred by exosomes have recently been identified to have a significant role in endometriosis by modulating different proteins and their related genes. As a result, the current review focuses on exosomal micro-and-long noncoding RNAs that are involved in endometriosis disease. Furthermore, major molecular mechanisms linking corresponding RNA molecules to endometriosis development will be briefly discussed to better clarify the potential functions of exosomal noncoding RNAs in the therapy and diagnosis of endometriosis.

Molecular Mechanisms and Therapeutic Potential of Resolvins in Cancer - Current Status and Perspectives.

Resolvins are specialized pro-resolving mediators derived from omega-3 fatty acids that can suppress several cancer-related molecular pathways, including important activation of transcription parameters in the tumor cells and their microenvironment, inflammatory cell infiltration, cytokines as well as chemokines. Recently, an association between resolvins and an important anti-inflammatory process in apoptotic tumor cell clearance (efferocytosis) was shown. The inflammation status or the oncogene activation increases the risk of cancer development via triggering the transcriptional agents, including nuclear factor kappa-light-chain-enhancer of activated B cells by generating the pro-inflammatory lipid molecules and infiltrating the tumor cells along with the high level of pro-inflammatory signaling. These events can cause an inflammatory microenvironment. Resolvins might decrease the leukocyte influx into the inflamed tissues. It is widely accepted that resolvins prohibit the development of debris-triggered cancer via increasing the clearance of debris, especially by macrophage phagocytosis in tumors without any side effects. Resolvins D2, D1, and E1 might suppress tumor-growing inflammation by activation of macrophages clearance of cell debris in the tumor. Resolvin D5 can assist patients with pain during treatment. However, the effects of resolvins as anti-inflammatory mediators in cancers are not completely explained. Thus, based on the most recent studies, we tried to summarize the most recent knowledge on resolvins in cancers.

Cell membrane biomimetic nanoparticles in drug delivery.

Despite the efficiency of nanoparticle (NP) therapy, in vivo investigations have shown that it does not perform as well as in vitro. In this case, NP confronts many defensive hurdles once they enter the body. The delivery of NP to sick tissue is inhibited by these immune-mediated clearance mechanisms. Hence, using a cell membrane to hide NP for active distribution offers up a new path for focused treatment. These NPs are better able to reach the disease's target location, leading to enhanced therapeutic efficacy. In this emerging class of drug delivery vehicles, the inherent relation between the NPs and the biological components obtained from the human body was utilized, which mimic the properties and activities of native cells. This new technology has shown the viability of using biomimicry to evade immune system-provided biological barriers, with an emphasis on restricting clearance from the body before reaching its intended target. Furthermore, by providing signaling cues and transplanted biological components that favorably change the intrinsic immune response at the disease site, the NPs would be capable interacting with immune cells regarding the biomimetic method. Thus, we aimed to provide a current landscape and future trends of biomimetic NPs in drug delivery.

Biomimetic Nanovaccines: a Novel Approach in Immunization.

As the World Health Organization (WHO) declared, vaccines prevent an average of 2-3 million deaths yearly from diseases. However, effective prophylactic and therapeutic vaccines have yet to be developed for eradicating the deadliest diseases, viz., types of cancer, malaria, human immunodeficiency virus (HIV), and most serious microbial infections. Furthermore, scores of the existing vaccines have disadvantages, such as failure to completely stimulate the immune system, in vivo instability, high toxicity, need for the cold chain, and multiple administrations. Thus, good vaccine candidates need to be designed to elicit adaptive immune responses. In this line, the integration of sciences along with the use of various technologies has led to the emergence of a new field in vaccine production called biomimetic nanovaccines (BNVs). Given that, nanotechnology can significantly contribute to the design of such vaccines, providing them with enhanced specificity and potency. Nanoparticles (NPs) and biomimetic NPs (BNPs) are now exploited as the main carriers for drug delivery systems, especially BNPs, whose biological mimicry makes them escape the immune system and transport drugs to the desired target. The drug accordingly seeks to camouflage itself with the help of NPs and the membranes taken from cells in the human body, including red blood cells (RBCs), white blood cells (WBCs), platelets, and cancer cells, for more effective and ideal delivery. As BNPs have recently become the center of attention in vaccine design, this review deliberates on the advances in BNVs.

Macrophage efferocytosis in health and disease.

Creating cellular homeostasis within a defined tissue typically relates to the processes of apoptosis and efferocytosis. A great example here is cell debris that must be removed to prevent unwanted inflammatory responses and then reduce autoimmunity. In view of that, defective efferocytosis is often assumed to be responsible for the improper clearance of apoptotic cells (ACs). This predicament triggers off inflammation and even results in disease development. Any disruption of phagocytic receptors, molecules as bridging groups, or signaling routes can also inhibit macrophage efferocytosis and lead to the impaired clearance of the apoptotic body. In this line, macrophages as professional phagocytic cells take the lead in the efferocytosis process. As well, insufficiency in macrophage efferocytosis facilitates the spread of a wide variety of diseases, including neurodegenerative diseases, kidney problems, types of cancer, asthma, and the like. Establishing the functions of macrophages in this respect can be thus useful in the treatment of many diseases. Against this background, this review aimed to recapitulate the knowledge about the mechanisms related to macrophage polarization under physiological or pathological conditions, and shed light on its interaction with efferocytosis.

Clinical Utility of Soluble CD163 and its Diagnostic and Prognostic Value in a Variety of Neurological Disorders.

Nowadays, many people suffer from Neurological Diseases (NDs), particularly neurodegenerative diseases. Hence, there is an urgent need to discover new and more effective diagnostic and prognostic biomarkers as well as therapeutic strategies for the treatment of NDs. In this context, detecting biomarkers can provide helpful information on various levels of NDs. Up to now, there has been a lot of progress in recognizing these diseases, but they are not completely clear yet. NDs are associated with inflammatory conditions and there are several differences in NDs' immune biomarkers compared to normal conditions. Among these biomarkers, soluble CD163 (sCD163) levels (as a new biomarker) increase in biofluids, relating to the activation of macrophage/microglia and inflammation levels in NDs. ADAM17/TACE and ADAM10 are the responsible enzymes for producing sCD163 from macrophages. Increased shedding of CD163 is caused by inflammatory stimuli, and a function has been hypothesized for sCD163 in immunological suppression. When the body confronts an inflammation or infection, the concentration of sCD163 drives up. sCD163 is stable and can be easily quantified in the serum. In addition to its role as a biomarker, sCD163 can be a good modulator of adaptive immune suppression after stroke. sCD163, with a long half-life, has been proposed to be a surrogate for some critical markers such as Tumor Necrosis Factor-α (TNF- α). Furthermore, sCD163 production can be regulated by some regents/approaches such as zidovudine, nanotechnology, combination antiretroviral treatment, and aprepitant. Considering the importance of the issue, the critical role of sCD163 in NDs was highlighted for novel diagnostic and prognostic purposes.

Exosomal lncRNAs in gastrointestinal cancer.

Gastrointestinal cancer (GIC) remains a leading cause of morbidity and mortality worldwide. Unfortunately, these cancers are diagnosed in advanced metastatic stages due to lack of reliable biomarkers that are sufficiently specific and sensitive in early disease. There has been growing evidence that circulating exosomes can be used to diagnose cancer non-invasively with limited risks and side effects. Furthermore, exosomal long non-coding RNAs (lncRNAs) are emerging as a new class of promising biomarkers in cancer. This review provides an overview of the extraction and detection of exosomal lncRNAs with a focus on their potential role in GIC.

The Role of Gut Microbiota in Inflammatory Bowel Disease-Current State of the Art.

The human microbiome comprises the genomes of the microbiota that live on and within humans, such as protozoa, archaea, eukaryotes, viruses, and most bacteria. Gastrointestinal disorders such as inflammatory bowel disease, colon cancer, celiac disease, and irritable bowel syndrome can all be triggered by a change in gut flora. The alteration of the gut microbiota (also known as "gut dysbiosis") is affected by host genetics, nutrition, antibiotics, and inflammation, and it is associated with the development of inflammatory bowel disease (IBD). Also, intestinal epithelial dysfunction, altered autophagy, and immune hyperactivation are frequently detected in individuals with severe IBD, which may be attributed to impaired miRNA expression functions. While the exact mechanisms of how Gut Microbiota may cause IBD and intestinal epithelial dysfunction are still debated, recent data point toward the possibility that hormones, gender and miRNAs expression are modifiable contributors to IBD. This review summarizes the current evidence for an association between hormones, gender and miRNAs and Gut Microbiota in IBD and discusses potential mechanisms by which gut microbiota may impact IBD. The study also outlines critical unanswered topics that need to be solved to enhance IBD prevention and treatment in people with gut dysbiosis.

Understanding the regulation of "Don't Eat-Me" signals by inflammatory signaling pathways in the tumor microenvironment for more effective therapy.

INTRODUCTION: Receptor/ligand pair immune checkpoints are inhibitors that regulate immunity as vital "Don't Find-Me" signals to the adaptive immune system, additionally, the essential goals of anti-cancer therapy. Moreover, the immune checkpoints are involved in treatment resistance in cancer therapy. The immune checkpoints as a signal from "self" and their expression on healthy cells prevent phagocytosis. Cells (e.g., senescent and/or apoptotic cells) with low immune checkpoints, such as low CD47 and/or PD-L1, are phagocytosed, which is necessary for tissue integrity and homeostasis maintenance. In other words, cancer cells induce increased CD47 expression in the tumor microenvironment (TME), avoiding their clearance by immune cells. PD-L1 and/or CD47 expression tumors have also been employed as biomarkers to guide cure prospects. Thus, targeting innate and adaptive immune checkpoints might improve the influence of the treatments on tumor cells. However, the CD47 regulation in the TME stands intricate, so much of this process has stayed a riddle. In this line, less attention has been paid to cytokines in TME. Cytokines are significant regulators of tumor immune surveillance, and they do this by controlling the actions of the immune cell. Recently, it has been suggested that different types of cytokines at TME might cooperate with others that contribute to the regulation of CD47 and/or PD-L1. MATERIALS AND METHODS: The data were searched in available databases and a Web Search engine (PubMed, Scopus, and Google Scholar) using related keywords in the title, abstract, and keywords. CONCLUSION: Given the significant role of pro/anti-inflammatory signaling in the TME, we discuss the present understanding of pro/anti-inflammatory signaling implications in "Don't Eat-Me" regulation signals, particularly CD47, in the pathophysiology of cancers and come up with innovative opinions for the clinical transformation and personalized medicine.

The Regulation, Functions, and Signaling of miR-153 in Neurological Disorders, and Its Potential as a Biomarker and Therapeutic Target.

Treatment of neurological disorders has always been one of the challenges facing scientists due to poor prognosis and symptom overlap, as well as the progress of the disease process. Neurological disorders such as Huntington's, Parkinson's, Alzheimer's diseases, and Amyotrophic Lateral Sclerosis are very debilitating. Therefore, finding a biomarker is essential for early diagnosis and treatment goals. Recent studies have focused more on molecular factors and gene manipulation to find effective diagnostic and therapeutic biomarkers. Among these factors, microRNAs (miRNAs/ miRs) have attracted much attention. On the other hand, a growing correlation between miRNAs and neurological disorders has caused scientists to consider it as a diagnostic and therapeutic target. In this line, the miR-153 is one of the most important and highly conserved miRNAs in mice and humans, whose expression level is not only altered in neurological disorders but also improves neurogenesis. MiR-153 can regulate multiple biological processes by targeting various factors. Furthermore, the miR-153 expression also can be regulated by important regulators, such as long non-coding RNAs (e.g., KCNQ1OT1) and some compounds (e.g., Tanshinone IIA) altering the expression of miR-153. Given the growing interest in miR-153 as a biomarker and therapeutic target for neurological diseases as well as the lack of comprehensive investigation of miR-153 function in these disorders, it is necessary to identify the downstream and upstream targets and also it's potential as a therapeutic biomarker target. In this review, we will discuss the critical role of miR-153 in neurological disorders for novel diagnostic and prognostic purposes and its role in multi-drug resistance.

Statin-regulated phagocytosis and efferocytosis in physiological and pathological conditions.

Efferocytosis (clearance of apoptotic cells by phagocytosis without inducing inflammation and autoimmunity) is an important mechanism in the resolution of inflammatory processes. Efficient efferocytosis inhibits the accumulation of apoptotic cells/debris and maintains homeostasis before the onset of necrosis (secondary necrosis), which promotes inflammation or injury. Moreover, the detection and clearance of apoptotic cells can promote anti-inflammatory responses. Defective efferocytosis is involved in the pathogenesis of several diseases, such as atherosclerosis, chronic inflammation, autoimmunity and cancer. Statins are 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitors which exert cholesterol-lowering effects plus multiple pleiotropic properties, such as inhibition of inflammation and macrophage proliferation. Statins exhibit anti-inflammatory properties by reducing both the prenylation of signaling molecules with downregulation of gene expression and the expression of adhesion molecules, as well as the levels of cytokines and chemokines. Additionally, statins suppress the prenylation of GTPases, such as Rac-1, as a positive regulator of efferocytosis, and RhoA, as a negative regulator of efferocytosis. However, statins alter the membrane balance of Rho GTPases in efferocytosis toward Rac-1. Efferocytosis has modifiable targets, which can be exploited for the treatment of several diseases, although limited attention has been given to the mechanisms by which statins regulate efferocytosis and the resulting therapeutic implications. In this review, we will elaborate on the mechanisms underlying the modulation of apoptotic cell clearance by statins, which, in turn, inhibits uncontrolled inflammation and ensuing diseases.

Recent findings on the role of microRNAs in genetic kidney diseases.

BACKGROUND: MicroRNAs (miRNAs) are non-coding, endogenous, single-stranded, small (21-25 nucleotides) RNAs. Various target genes at the post-transcriptional stage are modulated by miRNAs that are involved in the regulation of a variety of biological processes such as embryonic development, differentiation, proliferation, apoptosis, inflammation, and metabolic homeostasis. Abnormal miRNA expression is strongly associated with the pathogenesis of multiple common human diseases including cardiovascular diseases, cancer, hepatitis, and metabolic diseases. METHODS AND RESULTS: Various signaling pathways including transforming growth factor-ß, apoptosis, and Wnt signaling pathways have also been characterized to play an essential role in kidney diseases. Most importantly, miRNA-targeted pharmaceutical manipulation has represented a promising new therapeutic approach against kidney diseases. Furthermore, miRNAs such as miR-30e-5p, miR-98-5p, miR-30d-5p, miR-30a-5p, miR-194-5p, and miR-192-5p may be potentially employed as biomarkers for various human kidney diseases. CONCLUSIONS: A significant correlation has also been found between some miRNAs and the clinical markers of renal function like baseline estimated glomerular filtration rate (eGFR). Classification of miRNAs in different genetic renal disorders may promote discoveries in developing innovative therapeutic interventions and treatment tools. Herein, the recent advances in miRNAs associated with renal pathogenesis, emphasizing genetic kidney diseases and development, have been summarized.

The regulation of efferocytosis signaling pathways and adipose tissue homeostasis in physiological conditions and obesity: Current understanding and treatment options.

Obesity is associated with changes in the resolution of acute inflammation that contribute to the clinical complications. The exact mechanisms underlying unresolved inflammation in obesity are not fully understood. Adipocyte death leads to pro-inflammatory adipose tissue macrophages, stimulating additional adipocyte apoptosis. Thus, a complex and tightly regulated process to inhibit inflammation and maintain homeostasis after adipocyte apoptosis is needed to maintain health. In normal condition, a specialized phagocytic process (efferocytosis) performs this function, clearing necrotic and apoptotic cells (ACs) and controlling inflammation. For efficient and continued efferocytosis, phagocytes must internalize multiple ACs in physiological conditions and handle the excess metabolic burden in adipose tissue. In obesity, this control is lost and can be an important hallmark of the disease. In this regard, the deficiency of efferocytosis leads to delayed resolution of acute inflammation and can result in ongoing inflammation, immune system dysfunction, and insulin resistance in obesity. Hence, efficient clearance of ACs by M2 macrophages could limit long-term inflammation and ensue clinical complications, such as cardiovascular disease and diabetes. This review elaborates upon the molecular mechanisms to identify efferocytosis regulators in obesity, and the mechanisms that can improve efferocytosis and reduce obesity-related complications, such as the use of pharmacological agents and regular exercise.

The cross-talk between soluble "Find me" and "Keep out" signals as an initial step in regulating efferocytosis.

The rapid clearance of apoptotic cells (ACs), known as efferocytosis, prompts the inhibition of inflammatory responses and autoimmunity and maintains homeostatic cell turnover by controlling the release of intracellular contents. The fast clearance of ACs requires professional and nonprofessional phagocytic cells that can accurately and promptly recognize ACs and migrate towards them. Cells undergoing apoptosis alarm their presence by releasing special soluble chemotactic factors, such as lactoferrin, that act as "Find me," "Keep out," or "Stay away" signals to recruit phagocytic cells, such as macrophages or prevent granulocyte migration. Efferocytosis effectively serves to prevent damage-associated molecular pattern release and secondary necrosis and inhibit inflammation/autoimmunity at the very first step. Since less attention has been given to the cross-talk and balance of "Find me" and "Keep out" signals released from ACs in efferocytosis, we set out to investigate the current knowledge of the roles of "Find me" and "Keep out" signals in the efferocytosis process.